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The concept of clean beauty lacks a precise definition and its defining attributes remain unclear. This study assesses the impact of clean beauty on Millennial and Generation Z consumers, identifies its main attributes, and provides a new index for determining products’ cleanness . To this end, 120 Korean participants were recruited; they used 10 cosmetic products and completed relevant questionnaires. Clean beauty awareness and product satisfaction were assessed from the cognitive and emotional perspectives. The Reliable Cleanness Score (RCS) was calculated using emotional product satisfaction. Participants’ preference for clean beauty products was correlated with engaged cosmetic shopping behaviors. The key clean beauty attributes were sustainability, safety, and ethicality—in that order. Machine learning-based regression analysis showed that objective and subjective data could be used to calculate the RCS, resulting in an R 2 value of .721. With the results of this study, manufacturers, retailers, and consumers will be able to predict RCS.

In this study, we estimated the contributions of carbonate mineral weathering to dissolved inorganic carbon (DIC) and carbonate-derived DIC to autochthonous particulate organic carbon (POC) in two temperate Korean rivers. We combined stoichiometric and stable carbon isotopic approaches to calculate the contribution of autochthonous POC, considering diverse riverine DIC sources. We collected surface water samples from May 2016 to May 2018 and analyzed the major ion composition of rivers along with the concentrations and stable carbon isotopes of DIC. Our estimates showed that the relative abundances of carbonate mineral weathering (0.41 ± 0.11 in the Geum River and 0.43 ± 0.07 in the Seomjin River) were only slightly lower than those of silicate mineral weathering (0.59 ± 0.1 in the Geum River and 0.57 ± 0.07 in the Seomjin River). The resulting percentage contributions of DIC derived from the carbonate mineral weathering to riverine autochthonous POC, if we consider the additional DIC sources of atmospheric and soil-derived CO2, were 10 ± 3 % in the Geum River and 2 ± 1 % in the Seomjin River. The calculated annual fluxes of carbonate-derived DIC for 2016–2018 were 23.2 ± 0.3 Gg C yr−1 in the Geum River and 1.1 ± 0.4 Gg C yr−1 in the Seomjin River. Moreover, the calculated annual fluxes of carbonate-derived POC were 3.6 ± 0.5 Gg C yr−1 in the Geum River and 0.1 ± 0.7 Gg C yr−1 in the Seomjin River. Accordingly, our study provides the first insight into the contribution of carbonate-derived DIC to riverine autochthonous POC in small temperate Korean river systems, dominated by silicate rocks.

Bovine mastitis (BM) has caused huge economic and financial losses in the dairy industry worldwide, with Staphylococcus aureus as one of its major pathogens. BM treatment still relies on antibiotics and its extensive use often generates methicillin-resistant S. aureus (MRSA) and mupirocin-resistant S. aureus (MuRSA). This study compared the antimicrobial resistance trend in coagulase-positive Stapholococci (CoPS) isolated from BM milk in conventional and organic dairy farms and checked prevalence of MRSA and MuRSA. A total of 163 presumptive Staphylococci were isolated, wherein 11 out of 74 from 4 conventional farms (CF1, CF2, CF3, CF4) and 17 out of 89 from 3 organic farms (OF1, OF2, OF3) exhibited coagulase activity. Multiplex-PCR amplification confirmed at least one coagulase-positive isolate from CF1, CF2, CF3, CF4, and OF1 as S. aureus, denoted by the presence of the nuc gene. Three isolates from CF2 contained the mecA gene, indicating MRSA prevalence, while the MuRSA gene marker, mupA, was not detected in any of the isolates. Antimicrobial testing showed that conventional farm isolates were more resistant to antibiotics, especially ampicillin and tetracycline. This suggests a risk of developing multidrug resistance in dairy farms if antibiotic use is not properly and strictly monitored and regulated.

We investigated dual carbon isotopes within the vertical water column at sites 67-1 and 67-2 of the western equatorial Indian Ocean to determine the source and age of particulate organic carbon (POC) and thus evaluated the contributions of modern and fossil (aged) POC. The concentration of POC ranged from 7 to 47.3 μgC L−1, δ13CPOC values ranged from –31.8 to –24.4‰, and Δ14CPOC values ranged from –548 to –111‰. Higher values of δ13CPOC and Δ14CPOC near the surface indicated an influence of autochthonous POC, whereas decreasing trends toward the bottom suggested a contribution of aged OC sources to the total POC pool. The contribution of fossil POC was lower near the surface, accounting for only 12% and 6% of the total POC at sites 67-1 and 67-2, respectively; however, in the deeper layers below 1,000 m, the contribution of fossil POC increased to 52% and 44% of the total POC at the two sites. Mechanisms for the increased contributions of fossil OC within deeper POC include the inflow of aged OC from sediments resuspended near slopes, the adsorption of old dissolved organic carbon in deep water masses, and the impact of aged OC that may originate from hydrothermal sources. This study highlights the importance of aged OC in the carbon cycle of the equatorial Indian Ocean.

The cortical actin cytoskeleton plays a role in maintaining intestinal epithelial integrity. Here the authors report that TRIM40, an E3 ligase, disrupts cortical actin formation and leads to loss of epithelial barrier integrity, and that genetic loss of TRIM40 is protective against experimental colitis in male mice.

The nucleolus is the traditional site for ribosomal RNA biogenesis. Here, the authors find that the nucleolus is a site of inflammatory pre-mRNA turnover and elucidated how immune homeostasis can be maintained by controlling inflammatory gene expression.

Abstract The global prevalence of metabolic diseases, such as obesity, diabetes, and atherosclerosis, is rapidly increasing and has now reached epidemic proportions. Chronic tissue inflammation is a characteristic of these metabolic diseases, indicating that immune responses are closely involved in the pathogenesis of metabolic disorders. However, the regulatory mechanisms underlying immunometabolic crosstalk in these diseases are not completely understood. Recent studies have revealed the multifaceted functions of semaphorins, originally identified as axon guidance molecules, in regulating tissue inflammation and metabolic disorders, thereby highlighting the functional coupling between semaphorin signaling and immunometabolism. In this review, we explore how semaphorin signaling transcends beyond merely guiding axons to controlling immune responses and metabolic diseases.

Abstract Background The degree to which a validated instrument is able to detect clinically significant change over time is an important issue for the better management of hip or knee replacement surgery. This study examines the internal responsiveness of the EQ-5D-3L, the Oxford Hip Score (OHS), and the Oxford Knee Score (OKS) by various methods. Data from NHS patient-reported outcome measures (PROMs) linked to the Hospital Episodes Statistics (HES) dataset (2009–2015) was analysed for patients who underwent primary hip surgery (N = 181,424) and primary knee surgery (N = 191,379). Methods Paired data-specific univariate responsiveness was investigated using the standardized response mean (SRM), the standardized effect size (SES), and the responsiveness index (RI). Multivariate responsiveness was furthermore examined using the defined capacity of benefit score (i.e. paired data-specific MCID), adjusting baseline covariates such as age, gender, and comorbidities in the Box-Cox regression models. The observed and predicted percentages of patient improvement were examined both as a whole and by the patients' self-assessed transition level. Results The results showed that both the OHS and the OKS demonstrated great univariate and multivariate responsiveness. The percentages of the observed (predicted) total improvement were high: 51 (54)% in the OHS and 73 (58)% in OKS. The OHS and the OKS showed distinctive differences in improvement by the 3-level transition, i.e. a little better vs. about the same vs. a little worse. The univariate responsiveness of the EQ-5D-3L showed moderate effects in total by Cohen’s thresholds. The percentages of improvement in the EQ-5D-3L were moderate: 44 (48)% in the hip and 42 (44)% for the knee replacement population. Conclusions Distinctive percentage differences in patients’ perception of improvement were observed when the paired data-specific capacity of benefit score was applied to examine responsiveness. This is useful in clinical practice as rationale for access to surgery at the individual-patient level. This study shows the importance of analytic methods and instruments for investigation of the health status in hip and/or knee replacement surgery. The study finding also supports the idea of using a generic measure along with the disease-specific instruments in terms of cross-validation.

Objectives In this paper, we aimed to investigate the evolving debate over border closure in Korea during the coronavirus disease 2019 (COVID-19) pandemic, to address the main themes associated with border closure, and to discuss the factors that need to be considered when making such decisions. Methods We collated and reviewed previously conducted review studies on border closures during infectious disease outbreaks to derive relevant themes and factors. Results According to our systematic review on border closures and travel restrictions, the effects of such containment efforts are limited. We suggest considering the following factors when determining whether to impose border closure measures: (1) disease characteristics, (2) timeliness of implementation, (3) transmission delay and the basic reproduction number, (4) globalization and pandemics, and (5) social and economic costs. Conclusions Our assessment indicates that the effects of border closures are at best temporary and limited. Alternative measures must be contemplated and implemented to suppress the spread of COVID-19 in particular and infectious diseases more broadly.

Sluggish lithium diffusion on the surface of Li metal anodes poses a fundamental challenge. Here the authors report a Li/Li22Sn5 alloy design to address this issue. The composite anode sustains stable Li stripping/plating cycling with a low overpotential of 20 mV under 30 mA cm−2 in a commercial carbonate electrolyte.

Human cytomegalovirus (HCMV) has evolved several mechanisms to evade the host immune response. Here, Park et al. show that HCMV-encoded US7 and US8 proteins bind TLR3 and TLR4 and facilitate TLR degradation by distinct mechanisms, including ER-associated and lysosomal degradation.

In this paper, in order to develop composition ceramics for an acoustic emission sensor application for nondestructive testing, Pb(Ni,Nb2/3)O3-Pb(Zr,Ti)O3-Pb(Mg,W)O3 [PNN-PZT-PMW] system ceramics were manufactured by conventional mixed oxide method using Li2CO3 and CaCO3 as sintering aids. Their microstructural, dielectric and piezoelectric properties were also investigated. At x = 0.0075 Sm, the substituted specimen sintered at 980 (°C), and high values of piezoelectric properties appeared: the dielectric constant (εr) of 2824, piezoelectric coefficient d33 of 630 [pC/N], planar electromechanical coupling factor kp of 0.665, piezoelectric voltage constant g33 of 25.2 [mV.m/N], and high Curie temperature (Tc) = 270 (°C), respectively. These values were applicable for devices such as acoustic emission sensor and ultrasonic transducer.

Objectives To estimate the relationship between patient characteristics and referral decisions made by musculoskeletal hubs, and to assess the possible impact of an evidence-based referral tool.Design Retrospective analysis of medical records and decision tree model evaluating policy changes using local and national data.Setting One musculoskeletal interface clinic (hub) in England.Participants 922 adults aged ≥50 years referred by general practitioners with symptoms of knee or hip osteoarthritis.Interventions We assessed the current frequency and determinants of referrals from one hub and the change in referrals that would occur at this centre and nationally if evidence-based thresholds for referral (Oxford Knee and Hip Scores, OKS/OHS) were introduced.Main outcome measure OKS/OHS, referrals for surgical assessment, referrals for arthroplasty, costs and quality-adjusted life years.Results Of 110 patients with knee symptoms attending face-to-face hub consultations, 49 (45%) were referred for surgical assessment; the mean OKS for these 49 patients was 18 (range: 1–41). Of 101 hip patients, 36 (36%) were referred for surgical assessment (mean OHS: 21, range: 5–44). No patients referred for surgical assessment were above previously reported economic thresholds for OKS (43) or OHS (45). Setting thresholds of OKS ≤31 and OHS ≤35 might have resulted in an additional 22 knee referrals and 26 hip referrals in our cohort. Extrapolating hub results across England suggests a possible increase in referrals nationally, of around 13 000 additional knee replacements and 4500 additional hip replacements each year.Conclusions Musculoskeletal hubs currently consider OKS/OHS and other factors when making decisions about referral to secondary care for joint replacement. Those referred typically have low OHS/OKS, and introducing evidence-based OKS/OHS thresholds would prevent few inappropriate (high-functioning, low-pain) referrals. However, our findings suggest that some patients not currently referred could benefit from arthroplasty based on OKS/OHS. More research is required to explore other important patient characteristics currently influencing hub decisions.

In this study, surface water samples were collected at sites located in the lowest reaches of closed (Geum) (i.e. with an estuary dam at the river mouth) and open (Seomjin) estuary systems between May 2016 and May 2018. We analyzed concentrations and stable isotopes of particulate organic carbon (POC) and dissolved organic carbon (DOC) to assess OC sources, to estimate fluxes of riverine OC, and to assess some of the factors driving OC exports in these two contrasting Korean estuary systems. Our geochemical results suggest that the contribution of the phytoplankton-derived POC to the total POC pool was larger in the Geum River than in the Seomjin River. Notably, a heavy riverine algae bloom occurred in the Geum River in August 2016, resulting in a high carbon isotopic composition (−19.4‰) together with low POC/PN ratio (

Abstract Chronic obstructive pulmonary disease (COPD) has been recently characterized as a disease of accelerated lung aging, but the mechanism remains unclear. Tetraspanins have emerged as key players in malignancy and inflammatory diseases. Here, we found that CD9/CD81 double knockout (DKO) mice with a COPD-like phenotype progressively developed a syndrome resembling human aging, including cataracts, hair loss, and atrophy of various organs, including thymus, muscle, and testis, resulting in shorter survival than wild-type (WT) mice. Consistent with this, DNA microarray analysis of DKO mouse lungs revealed differential expression of genes involved in cell death, inflammation, and the sirtuin-1 (SIRT1) pathway. Accordingly, expression of SIRT1 was reduced in DKO mouse lungs. Importantly, siRNA knockdown of CD9 and CD81 in lung epithelial cells additively decreased SIRT1 and Foxo3a expression, but reciprocally upregulated the expression of p21 and p53, leading to reduced cell proliferation and elevated apoptosis. Furthermore, deletion of these tetraspanins increased the expression of pro-inflammatory genes and IL-8. Hence, CD9 and CD81 might coordinately prevent senescence and inflammation, partly by maintaining SIRT1 expression. Altogether, CD9/CD81 DKO mice represent a novel model for both COPD and accelerated senescence.

MAVS and STING signaling are central to interferon-inducing antiviral immunity. Here, the authors show how the human cytomegalovirus protein US9 can evade this immunity by antagonizing these pathways.

Recently, the need has arisen to enhance the piezoelectric properties and temperature stability of (Na,K)NbO3 system ceramics. The (0.965)(Li0.03(Na0.5K0.5)0.97)(Nb1−xSbx)O3−0.035 (Bi0.5Na0.5)0.9(Sr)0.1ZrO3 ceramics were newly manufactured using the sintering aids of CuO, B2O3, and ZnO as a function of antimony substitution, and the their crystal structure and electrical characteristics were analyzed. The grain size was apparently refined as the amount of antimony increased. The dielectric constant was enhanced and Curie temperature was decreased due to the content of the antimony substitution. The x = 0.07 sample sintered at 1060 °C presented the best electrical characteristics, which were bulk density = 4.488 g/cm3, piezoelectric constant d33 = 330 pC/N, electromechanical coupling factor kp = 0.427, mechanical coupling factor Qm = 61, and dielectric constant εr = 2521. We believe that the x = 0.07 sample is the best material for piezoelectric speakers.

The role of nutrient-sensing pathways in regulation of innate immune response is unexplored. Here the authors show that IL-4 activates the amino-acid sensing pathway in macrophages and leads to polarization of anti-inflammatory M2 macrophages via the transcription factor liver X receptor.

Background: There is no good evidence to support the use of patient-reported outcome measures (PROMs) in setting preoperative thresholds for referral for hip and knee replacement surgery. Despite this, the practice is widespread in the NHS. Objectives/research questions: Can clinical outcome tools be used to set thresholds for hip or knee replacement? What is the relationship between the choice of threshold and the cost-effectiveness of surgery? Methods: A systematic review identified PROMs used to assess patients undergoing hip/knee replacement. Their measurement properties were compared and supplemented by analysis of existing data sets. For each candidate score, we calculated the absolute threshold (a preoperative level above which there is no potential for improvement) and relative thresholds (preoperative levels above which individuals are less likely to improve than others). Owing to their measurement properties and the availability of data from their current widespread use in the NHS, the Oxford Knee Score (OKS) and Oxford Hip Score (OHS) were selected as the most appropriate scores to use in developing the Arthroplasty Candidacy Help Engine (ACHE) tool. The change in score and the probability of an improvement were then calculated and modelled using preoperative and postoperative OKS/OHSs and PROM scores, thereby creating the ACHE tool. Markov models were used to assess the cost-effectiveness of total hip/knee arthroplasty in the NHS for different preoperative values of OKS/OHSs over a 10-year period. The threshold values were used to model how the ACHE tool may change the number of referrals in a single UK musculoskeletal hub. A user group was established that included patients, members of the public and health-care representatives, to provide stakeholder feedback throughout the research process. Results: From a shortlist of four scores, the OHS and OKS were selected for the ACHE tool based on their measurement properties, calculated preoperative thresholds and cost-effectiveness data. The absolute threshold was 40 for the OHS and 41 for the OKS using the preferred improvement criterion. A range of relative thresholds were calculated based on the relationship between a patient’s preoperative score and their probability of improving after surgery. For example, a preoperative OHS of 35 or an OKS of 30 translates to a 75% probability of achieving a good outcome from surgical intervention. The economic evaluation demonstrated that hip and knee arthroplasty cost of

An amendment to this paper has been published and can be accessed via the original article.

While non-canonical, Atg5/Atg7-independent autophagy has been reported to occur, molecular details of alternative autophagy pathways remain unknown. Here, the authors report that the protein TRIM31 mediates alternative autophagy in intestinal cells, which protects against pathogenic bacteria.

The unique structure and physiology of a tumor microenvironment impede intra-tumoral penetration of chemotherapeutic agents. A novel iRGD peptide that exploits the tumor microenvironment can activate integrin-dependent binding to tumor vasculatures and neuropilin-1 (NRP-1)-dependent transport to tumor tissues. Recent studies have focused on its dual-targeting ability to achieve enhanced penetration of chemotherapeutics for the efficient eradication of cancer cells. Both the covalent conjugation and the co-administration of iRGD with chemotherapeutic agents and engineered delivery vehicles have been explored. Interestingly, the iRGD-mediated drug delivery also enhances penetration through the blood–brain barrier (BBB). Recent studies have shown its synergistic effect with BBB disruptive techniques. The efficacy of immunotherapy involving immune checkpoint blockades has also been amplified by using iRGD as a targeting moiety. In this review, we presented the recent advances in iRGD technology, focusing on cancer treatment modalities, including the current clinical trials using iRGD. The iRGD-mediated nano-carrier system could serve as a promising strategy in drug delivery to the deeper tumor regions, and be combined with various therapeutic interventions due to its novel targeting ability.

BackgroundCognitive stimulation therapy (CST) is a well-established group psychosocial intervention for people with dementia. There is evidence that home-based programmes of cognitive stimulation delivered by family caregivers may benefit both the person and the caregiver. However, no previous studies have evaluated caregiver-delivered CST. This study aimed to evaluate the effectiveness of a home-based, caregiver-led individual cognitive stimulation therapy (iCST) program in (i) improving cognition and quality of life (QoL) for the person with dementia and (ii) mental and physical health (well-being) for the caregiver.Methods and findingsA single-blind, pragmatic randomised controlled trial (RCT) was conducted at eight study sites across the United Kingdom. The intervention and blinded assessment of outcomes were conducted in participants' homes. Three hundred fifty-six people with mild to moderate dementia and their caregivers were recruited from memory services and community mental health teams (CMHTs). Participants were randomly assigned to iCST (75, 30-min sessions) or treatment as usual (TAU) control over 25 wk. iCST sessions consisted of themed activities designed to be mentally stimulating and enjoyable. Caregivers delivering iCST received training and support from an unblind researcher. Primary outcomes were cognition (Alzheimer's Disease Assessment Scale-cognitive [ADAS-Cog]) and self-reported QoL (Quality of Life Alzheimer's Disease [QoL-AD]) for the person with dementia and general health status (Short Form-12 health survey [SF-12]) for the caregiver. Secondary outcomes included quality of the caregiving relationship from the perspectives of the person and of the caregiver (Quality of the Carer Patient Relationship Scale) and health-related QoL (European Quality of Life-5 Dimensions [EQ-5D]) for the caregiver. Intention to treat (ITT) analyses were conducted. At the post-test (26 wk), there were no differences between the iCST and TAU groups in the outcomes of cognition (mean difference [MD] = -0.55, 95% CI -2.00-0.90; p = 0.45) and self-reported QoL (MD = -0.02, 95% CI -1.22-0.82; p = 0.97) for people with dementia, or caregivers' general health status (MD = 0.13, 95% CI -1.65-1.91; p = 0.89). However, people with dementia receiving iCST rated the relationship with their caregiver more positively (MD = 1.77, 95% CI 0.26-3.28; p = 0.02), and iCST improved QoL for caregivers (EQ-5D, MD = 0.06, 95% CI 0.02-0.10; p = 0.01). Forty percent (72/180) of dyads allocated to iCST completed at least two sessions per week, with 22% (39/180) completing no sessions at all. Study limitations include low adherence to the intervention.ConclusionsThere was no evidence that iCST has an effect on cognition or QoL for people with dementia. However, participating in iCST appeared to enhance the quality of the caregiving relationship and caregivers' QoL.Trial registrationThe iCST trial is registered with the ISRCTN registry (identified ISRCTN 65945963, URL: DOI 10.1186/ISRCTN65945963).

Aminoacyl-tRNA synthetase complex-interacting multifunctional protein 1 (AIMP1)-derived peptide (AdP) has been developed as a cosmeceutical ingredient for skin anti-aging given its fibroblast-activating (FA) and melanocyte-inhibiting (MI) functions. However, a suitable strategy for the topical delivery of AdP was required due to its low-permeable properties. In this study, FA and MI domains of AdP (FA-AdP and MI-AdP, respectively) were determined by functional domain mapping, where the activities of several fragments of AdP on fibroblast and melanocyte were tested, and a hydrosol-based topical delivery system for these AdP fragments was prepared. The excipient composition of the hydrosol was optimized to maximize the viscosity and drying rate by using Box-Behnken design. The artificial skin deposition of FA-AdP-loaded hydrosol was evaluated using Keshary-Chien diffusion cells equipped with Strat-M membrane (STM). The quantification of the fluorescent dye-tagged FA-AdP in STM was carried out by near-infrared fluorescence imaging. The optimized hydrosol showed 127-fold higher peptide deposition in STM than free FA-AdP (p < 0.05). This work suggests that FA- and MI-AdP are active-domains for anti-wrinkle and whitening activities, respectively, and the hydrosol could be used as a promising cosmetic formulation for the delivery of AdPs to the skin.

Nature Communications 7 Article number: 13130 (2016); Published 12 October 2016; Updated 27 February 2017 In this Article, there are errors in the labelling of the x axis in Fig. 5g,h that were introduced during the production process. The second label on the x axis of each graph in Fig. 5g should have been ‘ΦWT’ instead of ‘ΦKO’.

Background: Group cognitive stimulation therapy programmes can benefit cognition and quality of life for people with dementia. Evidence for home-based, carer-led cognitive stimulation interventions is limited. Objectives: To evaluate the clinical effectiveness and cost-effectiveness of carer-delivered individual cognitive stimulation therapy (iCST) for people with dementia and their family carers, compared with treatment as usual (TAU). Design: A multicentre, single-blind, randomised controlled trial assessing clinical effectiveness and cost-effectiveness. Assessments were at baseline, 13 weeks and 26 weeks (primary end point). Setting: Participants were recruited through Memory Clinics and Community Mental Health Teams for older people. Participants: A total of 356 caregiving dyads were recruited and 273 completed the trial. Intervention: iCST consisted of structured cognitive stimulation sessions for people with dementia, completed up to three times weekly over 25 weeks. Family carers were supported to deliver the sessions at home. Main outcome measures: Primary outcomes for the person with dementia were cognition and quality of life. Secondary outcomes included behavioural and psychological symptoms, activities of daily living, depressive symptoms and relationship quality. The primary outcome for the family carers was mental/physical health (Short Form questionnaire-12 items). Health-related quality of life (European Quality of Life-5 Dimensions), mood symptoms, resilience and relationship quality comprised the secondary outcomes. Costs were estimated from health and social care and societal perspectives. Results: There were no differences in any of the primary outcomes for people with dementia between intervention and TAU [cognition: mean difference –0.55, 95% confidence interval (CI) –2.00 to 0.90; p-value = 0.45; self-reported quality of life: mean difference –0.02, 95% CI –1.22 to 0.82; p-value = 0.97 at the 6-month follow-up]. iCST did not improve mental/physical health for carers. People with dementia in the iCST group experienced better relationship quality with their carer, but there was no evidence that iCST improved their activities of daily living, depression or behavioural and psychological symptoms. iCST seemed to improve health-related quality of life for carers but did not benefit carers’ resilience or their relationship quality with their relative. Carers conducting more sessions had fewer depressive symptoms. Qualitative data suggested that people with dementia and their carers experienced better communication owing to iCST. Adjusted mean costs were not significantly different between the groups. From the societal perspective, both health gains and cost savings were observed. Conclusions: iCST did not improve cognition or quality of life for people with dementia, or carers’ physical and mental health. Costs of the intervention were offset by some reductions in social care and other services. Although there was some evidence of improvement in terms of the caregiving relationship and carers’ health-related quality of life, iCST does not appear to deliver clinical benefits for cognition and quality of life for people with dementia. Most people received fewer than the recommended number of iCST sessions. Further research is needed to ascertain the clinical effectiveness of carer-led cognitive stimulation interventions for people with dementia. Trial registration: Current Controlled Trials ISRCTN65945963. Funding: This project was funded by the National Institute of Health Research (NIHR) Health Technology Assessment (HTA) programme and will be published in full in Health Technology Assessment; Vol. 19, No. 64. See the NIHR Journals Library website for further information.

Protection against endothelial damage is recognized as a frontline approach to preventing the progression of cytokine release syndrome (CRS). Accumulating evidence has demonstrated that interleukin-6 (IL-6) promotes vascular endothelial damage during CRS, although the molecular mechanisms remain to be fully elucidated. Targeting IL-6 receptor signaling delays CRS progression; however, current options are limited by persistent inhibition of the immune system. Here, we show that endothelial IL-6 trans-signaling promoted vascular damage and inflammatory responses via hypoxia-inducible factor-1α (HIF1α)–induced glycolysis. Using pharmacological inhibitors targeting HIF1α activity or mice with the genetic ablation of gp130 in the endothelium, we found that inhibition of IL-6R (IL-6 receptor)–HIF1α signaling in endothelial cells protected against vascular injury caused by septic damage and provided survival benefit in a mouse model of sepsis. In addition, we developed a short half-life anti-IL-6R antibody (silent anti-IL-6R antibody) and found that it was highly effective at augmenting survival for sepsis and severe burn by strengthening the endothelial glycocalyx and reducing cytokine storm, and vascular leakage. Together, our data advance the role of endothelial IL-6 trans-signaling in the progression of CRS and indicate a potential therapeutic approach for burns and sepsis. [ABSTRACT FROM AUTHOR]